This invention relates to a method for increasing the intestinal absorption, cellular concentration, biliary secretion, hepatic storage, and/or liver concentration of a fat soluble vitamin in a post-menopausal woman or a lower animal by orally administering L-carnitine and a fat soluble vitamin.
L-carnitine plays a crucial role in the energy supply of tissues by modulating the entry of long-chain fatty acids into the mitochondrial matrix and their subsequent oxidation. Consistent with such a metabolic role, L-carnitine has been shown to be effective in lowering the serum levels of cholesterol, triglyceride, and free fatty acids, while increasing high density lipoprotein (HDL) cholesterol which is antiatherogenic. See Pola, P. et al., xe2x80x9cCarnitine in the theraphy of dyslipemic patientsxe2x80x9d, Curr Ther Res 27:208-16 (1980); Lacour, B. et al., xe2x80x9cCarnitine improves lipid abnormalies in haemodialysis patientsxe2x80x9d, Lancet 12:763-4 (1980); Avogaro, P., xe2x80x9cAcute effect of L-carnitine on FFA and beta-hydroxy-butyrate in manxe2x80x9d, Pharmacol Res Commun 13:433-50 (1981); and Vacha, G. M. et al. xe2x80x9cFavourable effects of L-carnitine treatment on hypertriglyceridemia in hemodialysis patients: Decisive role of low levels of high density lipoprotein cholesterolxe2x80x9d, Am J Clin Nutr 38:532-40 (1983). Existing evidence indicates that L-carnitine and its esters enhance the stability and integrity of erythrocyte membranes by participating in the reacylation (repair) of membrane phospholipids subjected to oxidative damage. See Arduini, A. et al., xe2x80x9cEffect of propionyl-L-carnitine treatment on membrane phospholipid fatty acid turnover in diabetic rat erythrocytesxe2x80x9d, Mol Cell Biochem 152:31-7 (1995); Arduini, A. et al., xe2x80x9cCarnitine palmitoyltransferase and acyl-CoA binding protein: two more players in the membrane phospholipid fatty acid turnover of human red cells?xe2x80x9d, Biochem J 325:811-4 (1997); and Arduini, A. et al., xe2x80x9cAddition of L-carnitine to additive solution-suspended red cells stored at 4xc2x0 C. reduces in vitro hemolysis and improves in vivo viabilityxe2x80x9d, Trandfusion 37:166-74 (1997). It is of interest to note that such an action of L-carnitine and its esters is shown in the erythrocyte devoid of mitochondrial. L-carnitine supplementation to old rats has been shown to reverse the age-related decline in mitochondrial function, which may be linked to the membrane-stabilizing effect of L-carnitine. See Hagen, T. M. et al., xe2x80x9cAcetyl-L-carnitine fed to old rats partially restores mitochondrial function and ambulatory activityxe2x80x9d, Proc Natl Acad Sci USA 95:9562-6 (1998). This finding is of particular significance in that oxidative damage to mitochondrial DNA increases markedly with age, leading to impaired cellular metabolism and function. See Hagen, T. M. et al., xe2x80x9cMitochondrial decay in hepatocytes from old rats: membrane potential declines, heterogeneity and oxidants increasexe2x80x9d, Proc Natl Acad Sci USA 94:3064-9 (1997).
Postmenopausal women make up over 15% of the total population in industrialized countries. By 2030, the proportion of postmenopausal women is predicted to increase to 23% of the total population. See Hill, K., xe2x80x9cThe demography of menopausexe2x80x9d, Maturitas 23:113-127 (1996). In addition, numerous epidemiological studies have shown that depletion of estrogen at the menopause influences cause-specific morbidity and mortality in later life. From the nutritional standpoint, the menopause is the time when the body""s ability to absorb, assimilate, and metabolize nutrients begins to deteriorate. Consequently, the body status of nutrients is compromised at and after menopause, with the manifestations of specific nutrient deficiency symptoms with time.
It is well documented that postmenopausal women are substantially more susceptible to coronary heart disease, age-related macular degeneration, osteoporosis, cancer, and Alzheimer""s disease. See Hill, K., xe2x80x9cThe demography of menopausexe2x80x9d, Maturitas 23:113-127 (1996). Although this is partly associated with the process of aging and deterioration of bodily functions and the immune systems, epidemiological evidence suggests that a significant association exists between the risks (or incidence) of certain chronic diseases and the inadequacies or deficiencies of specific nutrients in postmenopausal women. Current evidence strongly suggests that the compromised body status of lipid-soluble vitamins, such as vitamins A, D, and E, is a key factor influencing or contributing to the onset or development of the diseases. For example, the risk of coronary heart disease rises dramatically in postmenopausal and ovariectomized women, compared with women in their child-bearing years. Supplemental vitamin E has been shown to reduce significantly the risk of coronary heart disease by retarding the oxidation of serum lipoproteins and inhibiting the proliferation of vascular smooth muscle cells. See Chan, A. C., xe2x80x9cVitamin E and atherosclerosisxe2x80x9d, J Nutr 128:1593-6 (1998); Motoyama, T. et al., xe2x80x9cVitamin E administration improves impairment of endothelium-dependent vasodilation in patients with coronary spasmic anginaxe2x80x9d, J Am Coll Cardiol 32:1672-9 (1998); and Meydani, M. et al., xe2x80x9cThe effect of long-term dietary supplementation with antioxidantsxe2x80x9d, Ann NY Acad Sci 854:352-60 (1998). Also, it is well established that vitamin D deficiency is prevalent in postmenopausal women with increased risk for bone loss and osteoporosis. See WHO Scientific Group, xe2x80x9cResearch on the menopause in the 1990sxe2x80x9d, WHO Technical Report, Series 866, 1996, WHO, Geneva, Switzerland. Also, studies have shown that the incidence of age-related macular degeneration in postmenopausal women is inversely correlated with intakes of provitamin A (carotenoids) and vitamin E. See Seddon, J. M. et al., xe2x80x9cDietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye disease case-control study groupxe2x80x9d, JAMA 272:1413-20 (1994); West, S. et al., xe2x80x9cAre antioxidants or supplements protective for age-related macular degeneration?xe2x80x9d, Arch Opthalmol 112:222-7 (1994); Van der Hagen, A. M., et al., xe2x80x9cFree radicals and antioxidant supplementation: a review of their roles in age-related macular degenerationxe2x80x9d, J Am Optom Assoc 64:871-8 (1993); and Golberg, J. et al., xe2x80x9cFactors associated with age-related macular degeneration. An analysis of data from first National Health and Nutrition Examination Surveyxe2x80x9d, Am J Epidemiol 128:700-10 (1988). Furthermore, recent evidence suggests that oxidative stress may play an important role in the pathogenesis of Alzheimer""s disease and that supplemental vitamin E may lower the risk of the disease. See Sinclair, A. J. et al., xe2x80x9cAltered plasma antioxidant status in subjects with Alzheimer""s disease and vascular dementiaxe2x80x9d, Int J Geriatr Psychiatry 13:840-5 (1998); Morris, M. C., et al., xe2x80x9cVitamin E and vitamin C supplement use and risk of incident Alzheimer diseasexe2x80x9d, Alzheimer Dis Assoc Disord 12:121-6 (1998); Subramaniam, R. et al., xe2x80x9cThe free radical antioxidant vitamin E protects cortical synaptosomal membranes from amyloid beta-peptide (25-35) toxicity but not from hydroxynonenal toxicity: relevance to the free radical hypothesis of Alzheimer""s diseasexe2x80x9d, Neurochem Res 23:1403-10 (1998).
It has also been shown that cancer accounts for 47% of disease-related deaths in dogs followed by heart diseases (12%) and kidney diseases (7%). In cats, top ranking diseases include cancer (32%), kidney/urinary diseases (23%), and heart diseases (9%). See Morris Animal Foundation Animal Health Survey 1997. It is thought that these diseases in animals are associated with inadequate levels of certain vitamins, especially antioxidant vitamins like vitamin E and vitamin C, as well as vitamin A.
Therefore, there is a need for improving the nutritional status of the fat-soluble vitamins in postmenopausal women, particularly, considering the decreased efficiency of nutrient absorption and deterioration of the intestinal absorptive function with aging in general. There is also a need for improving the nutritional status of the fat-soluble vitamins in lower animals, particularly, considering deterioration of the intestinal absorptive function with aging in general.
The present invention provides a method for increasing the intestinal (lymphatic) absorption, cellular concentration, biliary secretion, hepatic storage, and/or liver concentration of a fat soluble vitamin in a post-menopausal woman. The method comprises orally administering to a post-menopausal woman in need thereof, a fat soluble vitamin and a fat soluble vitamin absorption increasing effective amount of L-carnitine. The L-carnitine enhances the antioxidant defense mechanism and lowers the risk of certain degenerative diseases, such as coronary heart disease, age-related macular degeneration, osteoporosis, cancer, and Alzheimer""s, in post-menopausal women.
The invention also provides a method of reducing the risk of or preventing one or more diseases in a post-menopausal woman selected from coronary heart disease, agerelated macular degeneration, osteoporosis, cancer, and Alzheimer""s. The method comprises orally administering to a post-menopausal woman in need thereof, a fat soluble vitamin and a fat soluble vitamin absorption increasing effective amount of L-carnitine.
The invention provides a method for increasing the intestinal absorption of a fat soluble vitamin in an animal. The method comprises orally administering to the animal in need thereof, a fat soluble vitamin and a fat soluble vitamin absorption increasing effective amount of L-carnitine.
The invention also provides a method of reducing the risk of or preventing one or more diseases in an animal selected from heart diseases, including coronary heart disease; kidney diseases; urinary diseases; and cancer. The method comprises orally administering to an animal in need thereof, a fat soluble vitamin and a fat soluble vitamin absorption increasing effective amount of L-carnitine.